8/07/2009 @ 6:00AM

Merck's AIDS Triumph

Fifteen years ago, at the height of the AIDS epidemic,
Merck
researcher Daria Hazuda started work on a new drug to block the HIV virus from infiltrating people’s DNA.

The odds seemed grim.
Merck
executives at one point advised her to switch to an alternative approach being explored by rival
Pfizer
. And as new combinations of antiviral pill seemed to put the HIV virus in check, Hazuda herself wondered whether there was really a need for another AIDS drug. But she kept working, even as several attempts at creating the drug foundered in early tests.

Hazuda’s baby, Isentress, was approved in 2006 and was Merck’s fastest growing medicine last quarter. Sales of the twice-a-day pill jumped 123% to $172 million in the second quarter at a time when the overall U.S. drug market may shrink for the first time in decades. On July 9, the drug was approved as a choice for patients who are just beginning treatment. Timothy Anderson at Sanford C. Bernstein estimates sales could someday hit $2 billion a year.

“I’m glad we stuck with it,” says Hazuda, now Merck’s vice president of antiviral drugs. “We hear people say it has really changed their lives.”

The Isentress story turns the drug industry’s now-customary narrative–that small companies out-invent big ones–on its head. It’s also a reminder for Merck as it braces for the inevitable culture shocks likely to result from its $41 billion merger with
Schering-Plough
. The prospects of a new drug are precarious, with only one in nine drugs tested in humans making it to the market. Hundreds of millions of dollars, the work of hundreds of scientists and 10 years or more will go into the effort. Yet it’s often the grit and stamina of a single researcher that gets a medicine to patients.

Hazuda joined Merck in 1989 after finishing her doctorate at the State University of New York, Stony Brook. She was 30. Initially she was assigned to work on flu, but asked to be switched to HIV work. “If there was one virus worth working on, it was HIV,” she says.

In 1993, virus researcher and Nobel laureate Harold Varmus, who was just about to take over as head of the National Institutes of Health, called for researchers to search for drugs to target integrase–the enzyme that Isentress would attack.

HIV copies itself by splicing into the DNA of the people it infects and being copied when their cells replicate. Integrase is the enzyme that makes the cut. Block integrase, the logic went, and the virus could not spread from cell to cell. Aside from Merck, the companies now known as
GlaxoSmithKline
,
Sanofi-Aventis
and
Bristol-Myers Squibb
were all searching for integrase blockers.

The first challenge was figuring out how to measure whether or not chemicals were blocking the integrase enzyme so that hundreds of different potential medicines could be tried out. She and her small team of researchers succeeded in 1993, but couldn’t get any notice for their work. The Conference on Retroviruses and Opportunistic Infections, one of the biggest AIDS conferences rejected it, as did several big publications. The paper was finally published in 1994 in Nucleic Acids Research, a less prominent journal.

Then, in 1996, everything about HIV drug research changed. Results of studies combining three or four antiviral drugs at once were presented. These drug cocktails could keep HIV from ever developing into full-blown AIDS, in which the immune system fails. Scientists had commuted a death sentence.

Was there even a need for new HIV medicines? Hazuda herself was having doubts until she saw a Paul Volberding, a pioneering San Francisco doctor who had started the first program in the U.S. dedicated to treating AIDS, tell the story of a patient who had died despite the new drug cocktails. New drugs were still needed.

Just as she was getting back to work, researchers found a mutation in prostitutes and gay men that protected them from HIV infection. Other companies, including Pfizer and Schering-Plough, started developing drugs to target the gene, called CCR5. “Very senior management said I should stop working on integrase and start working on CCR5 inhibitors,” Hazuda says. But she insisted the right target was integrase, part of the virus, not CCR5, which is part of the patient.

Hazuda went back to her West Point, Pa., lab. But she couldn’t get her drug screen for integrase blockers to work with the robots Merck had at the time. In the summer of 1999, she and two associates squirted 250,000 different compounds by hand into plates containing the integrase enzyme. A chemical from xylaria, a fungus that grows on dead wood, blocked it. The molecule was too complicated to make into a drug, but, Hazuda says, “It provided a glimmer of hope.”

Finally, a few chemicals looked like they might work. In 2000 Hazuda and her team published two landmark papers showing that integrase inhibitors could be made. The first four chemicals they tried fizzled out in early studies. The fifth was a chemical synthesized by Merck researchers in Rome who were searching for hepatitis C drugs. That became Isentress.

Isentress was approved in 2007 for patients whose viral counts were rising despite AIDS drug therapy. Sales of Pfizer’s CCR5 drug are so small that the company doesn’t break them out, but a once-a-day drug from
Gilead
is advancing through clinical trials now.

What’s next? Recently Merck researchers found potential HIV drug targets by scanning the human genome. And Hazuda thinks there may be other ways to attack the virus too. “We haven’t run out of ideas,” she says. Merck better hope not.